PROBING THE MOLECULAR PROGRAM OF APOPTOSIS BY CANCER CHEMOPREVENTIVE AGENTS

This paper provides a rational molecular basis for studies intended to clarify the interactions between cancer chemopreventive agents and ap optosis, one of the natural forms of cell death that overlaps molecula r mechanisms with other forms such as programmed cell death and specia lized forms of physiological cell death. Molecular details of the proc ess show the existence of distinct molecular pathways leading to the a ctivation of critical effector elements (apaptosis gene products) func tioning under the control of a network of negative regulatory elements . Dysregulation of either apoptosis or anti-apoptosis genes has a sign ificant role in multistage carcinogenesis. Inhibition of apoptosis is one of the underlying mechanisms of the action of tumor promoters. The network of apoptosis and anti-apoptosis gene products provides multip le targets for compounds with cancer chemopreventive potential. Many d ata in the literature show initiating, potentiating or inhibitory effe cts of such compounds on apoptosis. However, the molecular mechanism o f these effects is largely unknown. We initiated a series of studies u sing mouse thymocytes which undergo apoptosis through distinct molecul ar mechanisms after T-cell receptor activation (TCR pathway), followin g the addition of glucocorticoids (DEX pathway) or DNA damaging agents (p53 pathway). All trans-and 9-cis-retinoic acid induced apoptosis, e licited through the DEX pathway, inhibited the TCR pathway, and did no t affect p53- initiated apoptosis. N-acetylcysteine can inhibit all fo rms. Sodium salicylate enhanced spontaneous cell death, decreased p53- dependent apoptosis, and did not affect the DEX and TCR pathways. Thes e preliminary results, which show differential effects of the studied compounds on distinct molecular pathways of apoptosis, warrant further investigations in the effort to utilize the molecular elements of apo ptosis in proper cancer chemoprevention, and find biochemical targets for apoptosis-related surrogate endpoint biomarker assays of chemoprev ention. (C) 1995 Wiley-Liss, Inc.